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. 2024 Mar 29;10(1):25.
doi: 10.1038/s41523-024-00629-3.

Automated mitotic spindle hotspot counts are highly associated with clinical outcomes in systemically untreated early-stage triple-negative breast cancer

Roberto A Leon-Ferre  1 , Jodi M Carter  2 , David Zahrieh  3 , Jason P Sinnwell  3 , Roberto Salgado  4   5 , Vera J Suman  3 , David W Hillman  3 , Judy C Boughey  3 , Krishna R Kalari  3 , Fergus J Couch  3 , James N Ingle  3 , Maschenka Balkenhol  6 , Francesco Ciompi  6 , Jeroen van der Laak  6   7 , Matthew P Goetz  3
Affiliations

Automated mitotic spindle hotspot counts are highly associated with clinical outcomes in systemically untreated early-stage triple-negative breast cancer

Roberto A Leon-Ferre et al. NPJ Breast Cancer. .

Abstract

Operable triple-negative breast cancer (TNBC) has a higher risk of recurrence and death compared to other subtypes. Tumor size and nodal status are the primary clinical factors used to guide systemic treatment, while biomarkers of proliferation have not demonstrated value. Recent studies suggest that subsets of TNBC have a favorable prognosis, even without systemic therapy. We evaluated the association of fully automated mitotic spindle hotspot (AMSH) counts with recurrence-free (RFS) and overall survival (OS) in two separate cohorts of patients with early-stage TNBC who did not receive systemic therapy. AMSH counts were obtained from areas with the highest mitotic density in digitized whole slide images processed with a convolutional neural network trained to detect mitoses. In 140 patients from the Mayo Clinic TNBC cohort, AMSH counts were significantly associated with RFS and OS in a multivariable model controlling for nodal status, tumor size, and tumor-infiltrating lymphocytes (TILs) (p < 0.0001). For every 10-point increase in AMSH counts, there was a 16% increase in the risk of an RFS event (HR 1.16, 95% CI 1.08-1.25), and a 7% increase in the risk of death (HR 1.07, 95% CI 1.00-1.14). We corroborated these findings in a separate cohort of systemically untreated TNBC patients from Radboud UMC in the Netherlands. Our findings suggest that AMSH counts offer valuable prognostic information in patients with early-stage TNBC who did not receive systemic therapy, independent of tumor size, nodal status, and TILs. If further validated, AMSH counts could help inform future systemic therapy de-escalation strategies.

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Conflict of interest statement

Roberto Leon-Ferre reports personal fees for CME activities from MJH Life Sciences and consulting fees paid to Mayo Clinic from Gilead Sciences, AstraZeneca, and Lyell Immunopharma. Matthew P Goetz is the Erivan K. Haub Family Professor of Cancer Research Honoring Richard F. Emslander, M.D. and reports personal fees for CME activities from Research to Practice, Clinical Education Alliance, Medscape, and MJH Life Sciences; personal fees serving as a panelist for a panel discussion from Total Health Conferencing and personal fees for serving as a moderator for Curio Science; consulting fees to Mayo Clinic from ARC Therapeutics, AstraZeneca, Biotheranostics, Blueprint Medicines, Lilly, Rna Diagnostics, Sanofi Genzyme, SymBioSis and Seattle Genetics; and grant funding to Mayo Clinic from Lilly, Pfizer, Atossa Therapeutics, AstraZeneca, and Sermonix. James N Ingle reports no COI. David Zahrieh reports no COI. Judy C Boughey is the W. H. Odell Professor of Individualized Medicine and reports personal fees for CME activities from MJH Life Sciences and EndoMag; honorarium from CairnsSurgical for DSMB work; royalty from UptoDate; consulting fees to Mayo Clinic from SymBioSis and grant funding to Mayo Clinic from Lilly. Jodi M Carter reports personal fees for consulting/advisory boards unrelated to the submitted work from Roche, Merck, Agilent and AstraZeneca. Francesco Ciompi and Jeroen van der Laak. are co-founders and shareholders of Aiosyn BV, The Netherlands. Francesco Ciompi was Chair of the Scientific and Medical Advisory Board of TRIBVN Healthcare, France, and received advisory board fees from TRIBVN Healthcare, France, in the last 5 years. Jeroen van der Laak was a member of the advisory boards of Philips, the Netherlands, and ContextVision, Sweden, and received research funding from Philips, the Netherlands, ContextVision, Sweden, and Sectra, Sweden, in the last 5 years. Maschenka Balkenhol is a medical advisor at Aiosyn BV, The Netherlands.

Figures

Fig. 1
Fig. 1. Effect of linear AMSH counts on recurrence-free survival (RFS) in each cohort.
Unadjusted (Model 1) and adjusted (Models 2–8) hazard ratios (HR) and 95% confidence intervals (CIs) are shown for different sets of potential confounding factors. Each Cox model considered in the Mayo Cohort (left panel) was repeated in the Radboud Cohort (right panel) to assess consistency in the magnitude of the HR and 95% CI. Based on purposeful covariate selection, the final model chosen was Model 3.
Fig. 2
Fig. 2. Survival outcomes according to AMSH count terciles in the Mayo Cohort.
A Recurrence-free survival. B Overall survival.
Fig. 3
Fig. 3. Survival outcomes according to AMSH count terciles in the Radboud Cohort.
A Recurrence-free survival. B Overall survival. Analyses were based on terciles determined in the Mayo Cohort.
Fig. 4
Fig. 4. Survival outcomes according to AMSH counts (<35 vs ≥35) and TILs (<30 vs ≥30) in the Mayo Cohort.
A Recurrence-free survival. B Overall survival.
Fig. 5
Fig. 5. Survival outcomes according to AMSH counts (<35 vs ≥35) and TILs (<30 vs ≥30) in the Radboud Cohort.
A Recurrence-free survival. B Overall survival.
Fig. 6
Fig. 6. Automatic Mitotic Spindle Hotspot counts workflow.
A Destained hematoxylin & eosin (H&E) slides are subsequently restained with phosphohistone-H3 (PHH3), which provides a rich contrast image without staining apoptotic figures. This image is subsequently registered to traditional H&E to allow mitosis detection independently of manual annotation. B Every detected mitotic figure is represented by a green dot. A 2 mm2 area with the highest density of mitotic figures is designated as a “hotspot” and circled in yellow. C The hotspot area as found by the deep learning algorithm at higher magnification. The blue rectangle within the yellow hotspot circle is magnified in D. D Mitotic figures found by the deep learning algorithm are circled in green. Two mitotic figures were missed by the algorithm (blue arrows, top right). Image modified from Tellez et al. and Balkenhol et al. and designed in part using Biorender.com.
See this image and copyright information in PMC

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